Cardiovascular disease is the leading cause of death in the United States and many other developed countries. A major contributing factor to cardiovascular disease is atherosclerosis, or the hardening of the arteries due to plaque formation. As atherosclerosis progresses, the blood vessels narrow and may close entirely. As a result, ischemia, or inadequate blood flow to tissues, can result and damage the affected tissue. In patients with coronary artery disease, ischemia in the heart can lead to severe chest pain, impaired cardiac function or, if very severe, heart attacks. Approximately 50% of deaths attributable to cardiovascular disease are due to coronary artery disease.
Treatment alternatives for coronary artery disease range from risk factor modification and exercise programs for patients with limited disease to major surgical procedures in severely diseased patients. Drug therapy is a mainstay of treatment for coronary artery disease. Surgical intervention such as angioplasty and/or stent placement are often used to open occluded vessels for patients with severe disease. Angioplasty procedures typically use an inflatable balloon catheter to physically open a narrowed blood vessel. Studies have shown that 30% to 40% of the time the artery narrows again, or undergoes restenosis within seven months following angioplasty. The procedure is difficult or impossible to perform on certain patients with multiple vessel disease, diffuse disease, calcified vessels or vessels that are too small to access. Stent placement has become a good alternative to angioplasty, but the challenges of re-occlusion of the stent have not been completely solved, and stents are not generally used to treat multiple occlusions. For patients with severe coronary artery blockages, the preferred treatment is still the coronary artery bypass graft surgery, in which the occluded coronary arteries are replaced with the patient's saphenous vein. The conventional CABG procedure requires cutting through the sternum of the chest and placing the patient on cardiopulmonary bypass, both of which involve significant risk of morbidity and mortality. In addition, it is difficult or impossible to perform CABG on certain patients with diffuse atherosclerotic disease or severe small vessel disease or patients who have previously undergone a CABG procedure.
Pacemakers provide another treatment for heart disease. Pacemakers with helical tipped active fixation leads have been in clinical use for greater than 25 years. Often when implantable leads become infected or fail due to fatigue, physicians will extract the entire body of the lead and leave behind the active fixation element which is buried in the myocardium. Furman S.; Hayes, D.; Holmes, D.: A Practice of Cardiac Pacing, Futura, Mount Kisco, N.Y., 3rd ed., 1993 shows an image of a patient with four separate abandoned intramyocardial electrodes in addition to two more additional electrodes for dual chamber pacing left behind in the heart with no apparent effect. It is well recognized that a helical intramyocardial implant remnant resulting from the extraction of a lead system poses no known risk to the patient.
Restoring blood flow to areas of ischemia through angiogenesis offers one of the most promising therapeutic options for treatment of coronary artery disease. Angiogenesis, or the formation of new blood vessels, is the body's natural response to ischemia. It also occurs as a normal physiological process during periods of tissue growth, such as an increase in muscle or fat, during the menstrual cycle and pregnancy, and during healing of wounds. Under ischemic conditions, expression of certain genes leads to the production of growth factors and other proteins involved in angiogenesis. The endothelial cells, which line blood vessels, contain receptors that bind to growth factors. Binding of the growth factors to these receptors triggers a complex series of events, including the replication and migration of endothelial cells to ischemic sites, as well as their formation into new blood vessels. However, in ischemic conditions, the growth factor genes often may not produce sufficient amounts of the corresponding proteins to generate an adequate number of new blood vessels. A logical therapeutic approach to this problem is to enhance the body's own response by temporarily providing higher concentrations of growth factors at the disease site. For cardiac disease, this will require a cardiovascular delivery system. Current delivery systems however are undesirable for a number of reasons.
One delivery system that has been proposed is the delivery of angiogenic agents through the coronary arteries. However, the extent of collateralization (growth of blood vessels elsewhere in the body, like the brain and lenses of the eye) observed is undesirable, so the dose provided must be less than desired. Delivery of recombinant growth factors bFGF and VEGF to the coronary arteries has entered Phase II human clinical trials, but the route of administration does not appear to be optimal. This is best shown by the recently completed VIVA phase II clinical trial in which rhVEGF 165 was delivered to both the coronary arteries and intravenously over periods of time, and yet did not show a statistically significant improvement in the patients who received the drug versus the placebo.
Additionally, arterial delivery treats the tissue subtended by the vessel with agents delivered to the most highly perfused tissue and rapidly washing away from the tissue. If agents are delivered to the coronary artery, the coronary artery bed, which includes richly and poorly perfused regions, will receive the drug therapy. Due to the nature of the restenosis or flow restriction, poorly perfused (ischemic) areas will receive less angiogenic agents, and healthy tissue will receive more. As the underlying problem of ischemic tissue is poor perfusion, excess growth factor must be delivered in order to obtain the desired effects in the poorly perfused tissue. Because of the high flow in the arteries, growth factor that is not bound by receptors in the vessels is quickly distributed to the rest of the body.
The pharmacokinetics of these clinical studies has not been discussed scientifically, yet it has been shown that sustained delivery is important to promote optimal angiogenesis. Gene therapy preparations are being used in the clinic to provide for sustained delivery of different forms of angiogenic agents VEGF and FGF to increase the magnitude of the therapeutic effect. Gene therapy currently suffers the difficulty that agents must be (1) delivered to the site, (2) gain access to the targeted cell cytosol, (3) become incorporated in the host cell's DNA, (4) be transcribed to produce mRNA, (5) the mRNA must be translated to produce the protein, and then (6) the protein must find a means of egress from the cytosol to the extracellular space in order to have its intended endogenous effects of promoting angiogenesis. At each of these six steps there are substantial efficiency issues that are difficult to control. There are currently three clinical trials entering Phase II studies in which the effective dose (step 6 of the cascade) of therapeutic protein that is being delivered to the tissue is not well understood.
Implantation of local drug delivery depots is an alternative to poorly controllable injection of gene therapy preparations. However, currently proposed depots pose difficulties. The processing steps needed to make them can render the therapeutic agent to be delivered biologically inactive. Nugent, M. A., Chen O. S., and Edelman, E. R., Controlled release of fibroblast growth factor: activity in cell culture. 252 Mat. Res. Soc. Symp. Proc.: 273 (1992) illustrates the difficulties in producing useful depots. They identified the problem with Ethylene Vinyl Acetate Copolymer (EVAC) delivery of bFGF as being attributable to the denaturation of nearly 95% of the protein by the organic solvents necessary to fabricate EVAC matrices. This means that for a desired dose, about 20 times the desired dose must be used to end up with an implant that carries the desired dose. Recently, these issues have been resolved for surgical delivery of bFGF by the successful surgical implantation through the epicardium of alginate encapsulated heparin sepharose controlled release depots in a phase I clinical trial. Sellke, et al. Therapeutic Angiogenesis with Basic Fibroblast Growth Factor: Technique and Early Results, 65 Annals Thoracic Surgery, 1540 (1998). Although this is by far the most advanced work done to date, the controlled release depots are too large (0.5 cm to 1.0 cm in diameter) to be delivered percutaneously by a catheter system. Their placement requires surgical access to the surface of the heart. It is also unlikely that the desired target area for these devices is epicardial or even endomyocardial as ischemic zones tend to be localized to the subendocardium. These issues limit this delivery approach, add risks to the patients who receive it, and increase the procedural costs of this delivery method.
Our own catheter systems with helical infusion needles for interstitial delivery provide for delivery of small controlled release structures such as microspheres (diameter=15 to 150 um) by transporting them through a fluid slurry to a depth within the heart with high efficiency. Our system reduces the potential of “back leak” or “squeeze out” of controlled release microsphere slurry or gel materials into the left ventricular chamber. These small controlled release systems have a very large surface-area-to-volume ratio, thus making it difficult to provide optimal release kinetics for many known microsphere systems, such as the Alkermes Prolease system. It can be difficult to achieve zero order release kinetics in which the dose is delivered at a constant rate over time. In addition, polymeric microspheres require formulation specific issues to be addressed for each agent that is to be delivered, and these can cause additional problems as already discussed.
If the drug releasing structure is implanted in the left ventricle from the endocardial surface, there is a danger that solid particles can escape into the arterial blood system and be pumped out to the body. These embolic particles could end up lodged in a vessel and occlude it, causing ischemia or necrosis to tissue elsewhere in the body. Another danger is that a proliferative agent, such as a growth factor, could embolize and be delivered to an unintended area of the body, such as the brain or the retina, where new uncontrolled blood vessel growth (angiogenesis) could damage healthy tissue. Therefore, there is a need for a structure that can deliver solid or degradable forms of therapeutic to a depth of the myocardium while lowering the risk for embolic events.